A number of clinical conditions involve (e.g., are caused by and/or themselves cause) impaired circulation, and particularly circulation within interstitial spaces and within discrete, localized tissues. Among the more vexing examples of such circulatory afflictions are osteonecrosis (e.g., avascular necrosis), compartment syndrome, and edema (and in particular, cerebral edema).
A number of conditions involve poor blood supply to the bone, leading to bone necrosis. Avascular necrosis of the proximal femur, for instance, is the disabling end result of a variety of disease processes that can affect patients of all ages. There is no treatment presently available that can predictably alter the natural history of the disorder. Clinical and radiographic progression to femoral head collapse occurs in approximately 80 percent of cases, and 50 percent undergo total hip replacement within three years. Numerous techniques have been attempted aimed at promoting the early revascularization of the femoral head, with the goal of reversing the usual process of joint deterioration. These approaches include muscle pedicle transfer and vascularized bone grafts.
Other methods, including bone remodeling and fracture repair are similar at the cellular level, and involve the coordinated delivery of a variety of cellular elements such as growth factors, such as transforming growth factor beta (TGF-beta), fibroblast growth factor (FGF) and bone morphogenetic protein. Several technical barriers to the treatment of AVN of the femoral head and neck include the limited blood supply of the site, difficult surgical access, and the accelerated progression of the disease due to biomechanical demands of walking on the hip joint.
Acute compartment syndrome generally involves impaired circulation within an enclosed fascial space, leading to increased tissue pressure and necrosis of muscle and nerves. The soft tissue of the lower leg is contained within four compartments, each bounded by heavy fascia—the anterior, lateral, superficial posterior, and deep posterior compartments. The anterior compartment holds the major structures for ankle dorsiflexion and foot and extension. Direct trauma, ischemia, or excessive, unaccustomed exercise can result in hemorrhage and swelling inside the anterior compartment. This swelling will increase pressure on the nerves, veins and arteries inside the compartment. Without arterial circulation, muscle cells will die. In addition, the prolonged compression of nerves can destroy their ability to function.
The neurovascular compression continues to worsen in the following symptoms: weakness or inability to dorsiflex the foot or extend the great toe, decreased ability of the peroneal tendon to evert the foot, and marked itching or prickling sensations in the web between the first and second toe or over the entire dorsal area of the foot. These symptoms must be identified quickly, since misdiagnosis can lead to permanent neuromuscular damage and physical disability.
Diagnosis involves clinical symptoms such as pain and swelling, and signs such as tense compartment pain on passive stretching, parathesia and decreased pulse, and increases in intracompartmental pressure. Once diagnosed, the injury requires immediate decompression through surgical release of the fascia covering the area. Others suggest treatment means include the use of a sympathetic blockade, hyperbaric oxygen therapy, and treatment with mannitol and/or alloperinol.
The characteristics of acute tissue edema are well known, and the condition continues to be a clinical problem, particularly since edema can be detrimental to the tissue as a result of disruption of the microcirculation. Tissue swelling results in increased diffusion distances, which in turn decreases interstitial nutrient delivery. Irreversible disruption of the microcirculatory system can occur as a result of unresolved acute injury. Resolution of tissue edema is problematic since natural mechanisms by which edema resolves are also affected by the edema. Edema compresses venules and lymphatic vessels, and inflammation makes lymphatic vessels hyperpermeable. Pharmacologic treatment is often not effective since blood borne agents have difficulty reaching their target tissue.
Cerebral edema (also known as brain swelling), includes vasogenic cerebral edema (most common form of edema) which manifests itself in the form of increased permeability of small vessels (breakdown of blood-brain barrier) and the escape of proteins and fluids into extracellular space, especially of white matter. Other forms of cerebral edema include cytotoxic cerebral edema (cellular brain edema) and interstitial edema.
Cerebral edema can be caused by ischemia, loss of oxygen, or focal disruption or loss of blood supply such as stroke. In the case of stroke, the specific area must be treated early to prevent further damage. The diagnosis of cerebral edema is based on changes in mental status, imaging, and measurement of intracranial pressure. Conventional treatment of cerebral edema is controversial. Some practictioners insist on keeping the blood pressure high to overcome high intracranial pressure, while others keep the blood pressure low in the hopes of limiting intracranial pressure. Opening the skull generally cannot be done to relieve pressure, because the brain tissue would herniate out the opening causing significant tissue damage. Giving intravenous treatments is also not effective because the brain microcirculation is disrupted so delivery to the brain is impaired.
Neurologic damage initiated by traumatic brain injury (TBI) continues to evolve over a period of hours to days following injury, due to deleterious delayed or secondary insults. The formation of cerebral edema, which, in turn, can lead to elevated intracranial pressure (ICP), is one of the most prevalent secondary insults serving to increase patient morbidity and mortality after TBI. ICP rises rapidly with the addition of a small intracranial fluid volume, due to the rigid and relatively inflexible nature of the skull. Complicating factors include relative noncompressability and constant volumes of brain tissue, blood, and cerebrospinal fluid (CSF) within the craniospinal intradural space. Brain swelling leading to dangerously elevated ICP develops in 40-50% of TBI patients with a Glascow Coma Scale (GCS) of 8 or less, and higher ICP levels have been repeatedly shown to lead to poor prognosis or outcome.
Monitoring of ICP is considered appropriate for all patients with severe TBI. While the placement of an ICP monitor is invasive, the benefits of ICP monitoring are felt to offset this factor, carry a relatively small risk of complications (e.g., infection, hemorrhage, malfunction, obstruction or malposition), and rarely result in increased patient morbidity. Percutaneous devices (e.g., ventriculostomy catheters) for use in monitoring ICP monitoring are commercially available in a variety of styles and from a number of sources. Such devices are commonly placed within the cerebral ventricles, where they enable accurate and reliable monitoring of ventricular pressure and can be used for the therapeutic convective drainage of CSF.
CSF drainage is described as a potentially effective method of lowering ICP, particularly when ventricular size has not been compromised. CSF drainage typically requires penetration of the brain parenchyma with a ventricular catheter. A variety of ventricular catheters are available for such purposes, e.g., the “MoniTorr” product available from CNS, Inc. As fluid is removed, however, brain swelling often progresses to the point where the ventricular system is compressed and the ability to drain CSF can be compromised. This may be exacerbated by overdrainage, leading to the ventricular walls or the choroid plexus actually collapsing in a manner that occludes the orifices of the catheter.
The therapeutic efficacy of convective CSF drainage by conventional ventriculostomy catheters, therefore, is limited. It has been shown that CSF can be removed from the ventricles in a manner that reduces the overall intracranial volume, and thus pressure. The fluid, however, is removed from the ventricle, not from the edematous brain tissue. Once the ventricular fluid has been removed, there is typically no further reduction in ICP. Also, ventriculostomy catheters can become occluded with tissue debris and clots during convective fluid removal.
In addition to the occasional therapeutic drainage of CSF via ventricular catheters there are three primary medical treatment strategies used in attempts to control cerebral edema elevated ICP in patients with severe TBI. As briefly outlined below, it can be seen that each of these therapeutic strategies is a “double-edged sword” since each treatment is typically associated with potential adverse consequences and each has limited efficacy.                Hyperventilation: Prophylactic hyperventilation of TBI patients is currently questioned since it has been reported to worsen outcomes, does not consistently reduce ICP, and may cause loss of autoregulation and potentiate secondary ischemia due to its actions on reducing cerebral blood flow.        Mannitol: This osmotic diuretic is currently the most widely used, and probably the safest, treatment for short-term control of elevated ICP in patients with TBI. Although it has become the cornerstone for control of elevated ICP after severe TBI, mannitol administration is not without risks. Careful monitoring and maintenance of serum osmolarity below 320 mOsm is needed to reduce the risk of acute renal failure, and the latter risk is potentiated in patients with sepsis or preexisting renal disease. Although the use of mannitol affects osmolarity within the site, this approach is not site-specific, rather, it is systemically administered. Since this approach is also chemically based, rather than device based, it does not employ a device that is itself provides an osmotic barrier.        Barbiturates: Prophylactic barbiturate therapy is currently discouraged, due to variable and unpredictable positive effects on ICP. Barbiturate therapy is now typically used only in hemodynamically stable patients with intracranial hypertension/elevated ICP that is refractory to all other therapeutic interventions.        
To date, osmotic fluid shifts in the course of TBI has received relatively little attention in the literature. Recent animal studies include one regarding CSF osmolality and the other regarding brain tissue osmolality (See C. Onal, et al., Acta Neurochir (Wien) 139:661-669 (1997). CSF osmolality was found to increase after a focal freeze injury in rats. CSF osmolality was found to increase from 277 mmol/kg to 348 mmol/kg at six hours after injury. CSF osmolality returned to 270 mmol/kg by 24 hours after injury. Interestingly, cerebral water content also increase at six hours, but remained elevated at 24 hours. Blood-brain barrier permeability also increased markedly at six hours and improved but remained elevated at 24 hours. Investigators in this study then went on to give intraventricular albumin to reduce the edema.
In the brain tissue study by Mori et al. J. Neurotrama 15:30 (1998), the osmolality was found to increase after cerebral contusion in a rat model. They found normal brain tissue osmolality to be 310 mmol/kg. Thirty minutes after injury, the tissue osmolality increased to 367 mmol/kg, and further increased to 402 mmol/kg at six hours. The investigators also compared ion concentration to total osmolality. On a separate topic, Janese (U.S. Pat. No. 4,904,237) describe the manner in which cerebral edema (i.e. water accumulation in brain tissue) constitutes one of the most severe and life threatening situations that occurs after traumatic brain injury (TBI) in humans. While edema can be controlled in many patients by the use of drug treatments, there are many patients for whom such treatment is not effective.
On a separate subject, Kanthan et al., J. Neuroscience Meth. 60:151-155 (1995), describe a method of in vivo microdialysis of the human brain, which method involves a “closed” technique in which a microdialysis probe and sheath are passed through a Codman bolt. Dialysate is withdrawn for periodic analysis. Similarly, Lehman et al., Acta Neurochir.[Suppl.], 67:66-69 (1996), describe a microdialysis probe for minimally invasive measurements of various products and metabolites in the brain. A number of other references describe various aspects and observations regarding the osmolar nature of brain fluids. See, for instance, Hossman, pp. 219-227 in “Dynamics of Brain Edema”, Pappius, et al., eds. (1976); Hatashita, et al., pp. 969-974 in “Intracranial Pressure VII”, Hoff et al. eds.; and Hoff et al., pp 295-301 in “Outflow of Cerebrospinal Fluid” (1989).
Yet other medical devices have been described which employ semipermeable membranes adapted to be implanted on a transitory basis, such as those presently used for “intracerebral microdialysis” in order to monitor rapid, ongoing chemical changes in the interstitial fluid (ISF). Such devices have been described as being potentially useful for examining neurochemical changes in the brains of patients with neurological disorders. Although analysis of brain ISF in this manner is still considered an invasive procedure, investigators have now demonstrated efficacy and safety of the technique in clinical situations. It would appear that several clinical research centers have begun using intracerebral microdialysis for monitoring the ISF within the past several years, and such monitoring has been employed in patients with TBI. To date, however, Applicant is unaware of any description of the use of such dialysis techniques or apparatuses in the treatment of cerebral edema or ICP.
In the course of inserting microdialysis probes into brain parenchyma, in order to monitor neurochemical alterations in patients, it has been found that there is minimal trauma to brain tissue and that complications are extremely rare. However, most, if not all, current microdialysis procedures rely on the slow, pump-driven infusion of dialysis fluid which travels through inlet lines past the dialysis fiber and then through outlet lines to enable collection of the dialysate. The dialysis probes used in such procedures are generally of rigid construction, to enable passage into brain tissue. The procedures themselves typically result in only a small percent “recovery” of neurochemicals or other molecular entities, for assay, since the procedures rely on the diffusion of chemicals from ISF to the dialysis fluid.
Investigators also commonly insert apparatuses into the brain ventricles, for a variety of reasons. Osterholm, for instance (U.S. Pat. Nos. 4,378,797, 4,445,500, 4,445,886, 4,758,431, and 4,840,617 ) describes a cerebral catheterization apparatus for delivering oxygenated nutrient to of from the CSF of a patient suspected of suffering from ischemia (stroke). The apparatus includes a catheter for providing an oxygenated nutrient, in the form of a synthetic CSF, to the ventricle. In view of the need to deliver (e.g., perfuse) such a nutrient to the brain quickly after stroke, this particular patent is directed toward a catheterization apparatus intended to be used by paramedics and emergency room personnel to insert a cerebral perfusion catheter into the left and right lateral brain ventricles of the patient.
The use of skin flaps has gained increased acceptance and use in the course of reconstructive and other forms of surgery. These techniques, however, continue to be plagued by problems having to do with survival of the skin flaps, which in turn, is believed to rely, at least in part, on efficient revascularization of the site. A number of approaches have been considered or evaluated for improving skin flap survival. See, for instance, Waters, et al., which provides a comparative analysis of the ability of five classes of pharmacological agents to augment skin flap survival in various models and species, in an attempt to standardize skin flap research. (Annals of Plastic Surgery. 23(2):117-22, 1989 August).
On a separate subject, the development of methods and apparatuses for tissue microdialysis began at least as early as the early 1960's with the work of Gaddum and others. To date, microdialysis has been used primarily, and with increasing frequency, in the neurosciences, as a means of assaying the interstitial space. In such applications the delivered solution is typically isotonic in order to avoid producing an osmotic gradient and resulting fluid shift. See, generally, Lonroth, et al., J Intern. Med., 1990 May; 227(5):295-300, “Microdialysis—A Novel Technique for Clinical Investigations”; Johansen, et al. Pharmacotherapy 1997 May; 17(3):464-481, “The Use of Microdialysis in Pharmacokinetics and Pharmacodynamics”; and Cimmino et al., Diabetes Metab. 1997 April; 23(2):164-170, “Tissue Microdialysis: Practical and Theoretical Aspects”.
A limited number of references describe the use of microdialysis to deliver substances such at therapeutic agents. Lehmarm et al., Acta Neurochir. Suppl., 67:66-69 (1996), describe a microdialysis probe adapted for entry into the parenchyma in order to measure various analytes, the probe being described as useful for possible “therapeutic applications”. Similarly, Yadid, et al., Am . J Physiol. 265: R1205-R1211 (1993), describe a modified microdialysis probe for sampling extracelluar fluid and delivering drugs for use in studying the local release and metabolism of neurotransmitters in vivo.
A limited number of other references describe the use of microdialysis to remove interstitial fluid for diagnostic purposes, as described, for instance in Linhares et al., Anal. Chem. 64:2831-2835 (1992). Recent articles have described the use of a hollow fiber catheter to perfuse the catheter with a hypertonic solution in order to intentionally produce a fluid shift and reduce tissue edema. See, for instance, Odland, et al. “Reduction of Tissue Edema by Microdialysis” Arch. Otolaryngol. Head Neck Surg, Vol. 121, pp. 662-666 (1995), which describes the use of a test device having catheters connected by afferent segments of tubing to an infusion pump providing a hypertonic solution of inulin in saline.
To Applicant's knowledge, however, there is no present teaching, let alone clinically acceptable approach for the application of tissue microdialysis in site specific therapy, or in particular, a microdialysis apparatus useful for prolonged periods, difficult sites, and in clinical settings.
In turn, current therapies for treating elevated ICP and cerebral edema, in humans with severe traumatic brain injury, have limited efficacy and continue to be associated with serious risks (particularly with prolonged use). In some patients, cerebral edema simply remains untreatable or nonresponsive to treatment. What is clearly needed are methods and related devices and systems for use in relieving ICP, particularly in a manner that optimizes the ability to employ conventional techniques and apparatuses, in new and different combinations, in order to improve overall patient outcome.